Sutures having long-lasting germicidal properties

ABSTRACT

Materials fabricated from fibrous proteins or other nitrogenous, amphoteric, film-forming, organic materials such as polymers, such as fibers, threads, films, yarns, fabrics and finished textile products, are provided with long-lasting germicidal properties by chemically combining germicidal ions with the nitrogenous, amphoteric, substrate. The germicidal ions are substantially incapable of being solvent extracted from the substrate which indicates that the ions have been chemically bonded thereto. For example, sutures, such as silk sutures, can be rendered germicidal for long periods of time by contacting a silk suture with an aqueous solution of a cationic or anionic germicidal surface active agent such as a germicidal quaternary ammonium salt or a germicidal organic sulfonate, to chemically bond the germicidal cation or anion of the salt to the proteinaceous substrate. The cationic or anionic germicidal agents can both be sequentially applied to the section containing both cationic and anionic germicidal ions bonded thereto.

United States Patent Kurtz Feb. 15, 1972 [54] SUTURES HAVINGLONG-LASTING GERMICIDAL PROPERTIES [72] Inventor: Leonard D. Kurtz,Woodmere, NY.

[73] Asslgnee: Sutures, Inc., Coventry, Conn.

[22] Filed: Aug. 26, 1969 [211 App]. No.: 853,200

Related US. Application Data [63] Continuation-in-part of Ser. No.737,340, June 17,

1968, abandoned.

FOREIGN PATENTS OR APPLICATIONS 835,933 4/1952 Germany ..128/335.5

Primary Examiner-Dalton L. Truluck Attorney-Larson and Taylor [57]ABSTRACT Materials fabricated from fibrous proteins or othernitrogenous, amphoteric, filmforming, organic materials such aspolymers, such as fibers, threads, films, yarns, fabrics and finishedtextile products, are provided with long-lasting germicidal propertiesby chemically combining germicidal ions with the nitrogenous,amphoteric, substrate. The germicidal ions are substantially incapableof being solvent extracted from the substrate which indicates that theions have been chemically bonded thereto. For example, sutures, such assilk sutures, can be rendered germicidal for long periods of time bycontacting a silk suture with an aqueous solution of a cationic oranionic germicidal surface active agent such as a ger micidal quaternaryammonium salt or a germicidal organic sulfonate, to chemically bond thegermicidal cation or anion of the salt to the proteinaceous substrate.The cationic or anionic germicidal agents can both be sequentiallyapplied to the section containing both cationic and anionic germicidalions bonded thereto.

9 Claims, N0 Drawings SUTURES HAVING LONG-LASTING GERMICIDAL PROPERTIESBACKGROUND OF THE INVENTION This is a continuation-in-part of mycopending application Ser. No. 737,340, filed June 17, 1968 nowabandoned.

The present invention relates to materials such as sutures havinglong-lasting germicidal properties. The invention further relates tomethods of providing such materials.

There have been several attempts to provide germicidal materials forgeneral and specific use. For example, U.S. Pat. Nos. 861,231, 1,741,893and 2,751,910 relate to the incorporation of germicides in surgicalsutures. U.S. Pat. No. 1,942,061 relates to the incorporation of agermicide in a wound dressing. Other patents relate to the incorporationof germicides in textiles generally and in such specific articles astoothbrushes, diapers, blankets, clothing, paper, leather and the like.For many uses, the germicides should be tenaciously held by thesubstrate to prevent rapid leaching and yet the germicide cannot be sointimately held that its germicidal activity is lost. The problem in theart has been to provide feasible techniques to make such materials withlong-lasting germicidal properties.

In my copending application Ser. No. 401,257, now U.S. Pat. No.3,388,704, I have described sutures having sustained microbiocidalactivity due to incorporation into the body of the suture of certaingermicides introduced into the suture by means of a solvent whichswelled the suture. ,Upon removal of the solvent, the germicides werelocked into the suture to SUMMARY OF THE PRESENT INVENTION According tothe present invention, 1 have discovered that sutures and othermaterials of a certain type can be provided with sustained germicidalactivity without the necessity of using the solvent swelling method orthe precipitation method of my copending applications. I have discoveredthat certain substrates which can be fabricated into useful articles,can be provided with long-lasting germicidal properties by chemicallycombining the substrate with a germicidal material. According to theinvention a nitrogenous, organic, amphoteric, film or fiber-formingsubstrate is contacted with an aqueous solution of a germicidal salthaving at least one germicidal ion, to provide the ions in intimateassociation with the substrate whereby germicidal ions become chemicallybonded to the substrate. The type of chemical bond formed is not known.However, the fact that chemical bonds are present is indicated by thefact that amounts of germicide picked up by the substrate in excess of afixed amount (which depends on the substrate and the ion in question)are readily extracted by washing with water whereas amounts below thatfinal amount are essentially nonextractable. The nature of the bond isnot known. However, the bond is not extremely strong because thesubstrate exhibits sustained germicidal activity which is presumed to bedue to the slow release of the germicidal material.

DETAILED DESCRIPTION OF THE INVENTION The substrate which is renderedgermicidal is an amphoteric, nitrogenous, organic, filmor fiber-formingmaterial. Preferred substrates comprise film-forming fibrous proteins ororganic polymers. Of the fibrous proteins, collagen and the silkprotein, fibroin, are preferred. Organic polymers such aspolyvinyl-pyrollidone and which are amphoteric are also suitable.

The articles treated are preferably films and textiles, includingfibers, threads, yarns, fabrics, both woven and nonwoven, and the like,including finished articles such as sutures, bandages, etc. Theinvention is particularly suited to providing sutures of silk andcollagen with longlasting germicidal properties.

The germicidal ion which is provided in the substrate can be either acation or an anion. The substrates according to the invention areamphoteric. That is, in their normal form they are capable of reactingwith either anions or cations. The germicidal ion is provided bydissolving a germicidal salt in an aqueous solution. Suitable cationicgermicidal salts are quatemaryammonium germicides and water-solublesalts of cationic antibiotics. Water-soluble quaternary ammoniumgermicides constitute a class of cationic salts well suited to theinvention. Typical among these salts are substituted to the invention.Typical among these salts are substituted and unsubstituted alkyldimethylbenzylammonium halides such as diisobutylphenoxyethoxyethyldimethyl benzyl ammonium chloride (benzethonium chloride) benzalkoniumchloride, lauryl-dimethylbenzylammonium chloride,cetyl-dimethylbenzylammonium chloride, and pyridinium salts such aslauryl pyridinium halides.

The water-soluble quaternary ammonium salts may be chosen from a groupof materials characterized by the formula:

wherein x may be any anion that does not render the salt waterinsoluble, e.g., chloride, bromide, sulfate, etc.: and wherein R is analiphatic hydrocarbon chain of at least eight carbon atoms which may bepart of a hereocyclic system together with other R radicals, saidhydrocarbon chains optionally being interrupted by oxygen, double bonds,nitrogen, and aromatic rings; and wherein the R' radicals are taken fromthe group consisting of lower alkyls of one to seven carbon atoms,aralkyl, alkenyl, alkoxy, polyalkoxy, and chloroalkyl.

Another class of high molecular weight germicidal cations can beobtained from salts of basic antibiotics. Suitable antibiotics includegentamicin and others classified as polypeptides and bases. Among thepolypeptides may be mentioned bacitracin, polymyxins, tyrothricin,viomycin and vancomycin. Bases include cycloserine, tetracycline,aureomycin. terramycin, subtilin and anisomycin. The antibiotic cationsare conveniently provided in aqueous solutions of the mineral acid saltsof the antibiotics.

The germicidal ion may also be an anion, such as the anion ofsulfonamide and derivatives thereof, salts of hexachlorophene, or othergermicidal anion or the anion of an anionic surfactant or of an organicacid. Germicidal anionic surfactants include organic sulfonates such asthe alkyl sodium sulfonates, aralkyl sodium sulfonates, monosulfonatesof monoglycerides, sulfonates of succinic esters, etc. By organic acidis meant an organic compound having acidic functional groups capable offorming salts with bases such as ammonium and alkali metal hydroxides.Thus, the term includes organic compounds containing other functionalgroups such as hydroxy but which react with bases though the acidfunction to form water-soluble salts. Among the many organic acidscontaining a suitable germicidal anion are the acid antibiotics such aspenicillins and fumagillin. The term "penicillins as used herein meansacid antibiotics which are structurally 6- substituted penicillanicacids such as Penicillins G, N, O, and V, nafcillin, methicillin,oxacillin and the like. As in the case of the cation, the anions areconveniently formed by providing an aqueous solution of the freematerial or water-soluble salts thereof, such as Penicillin G sodium andthe like.

Suitable germicidal anionic surfactants include: germicidal alkylsulfonates having the formula RSO X wherein R is an alkyl radical of 13to 18 carbon atoms and X is sodium or potassium; germicidal alkarylsulfonates having the formula RArSO -X wherein R is an alkyl radical of10 to 18 carbon atoms, X is sodium or potassium, and Ar represents adivalent aromatic hydrocarbon residue; monosulfates of monoglycerides;and sulfonates of succinic acid esters. More specifically, suitableanionic surfactants include dioctyl sodium sulfosuccinate, sodium laurylsulfate, sodium tetradecyl sulfate, sodium alkyl phenoxy sulfates, andtriethanolamine salts of fatty acids such as triethanolamine laurylsulfate.

The long-lasting germicidal ions can be readily provided in any of thenitrogenous substrate materials mentioned. The substrate is simplycontacted with an aqueous solution of the germicide salt. The aqueoussolution of the germicide salt. The aqueous solution may include aswelling agent which enhances impregnation into the substrate.,Theswelling agent may be the water of the aqueous solution, or it may be anadditional ingredient such as a polar organic solvent. The solution canbe heated to aid impregnation provided that the germicidal salt is notdestroyed by such heat.

The germicidal ions may be provided in clothing such as diapers, insurgical dressings, and sutures which comprise, at least in part, any ofthe mentioned nitrogenous substrate material.

The invention is further illustrated in the examples which follow.

EXAMPLE I A silk suture weighing about 1 gram is suspended in 100 ml. ofan aqueous solution containing 20 percent by weight benzethoniumchloride at room temperature. The solution is then heated to 100 C. andheld there for 15 minutes. The suture is then removed from the solutionand repeatedly washed with a total of several gallons of water. Thethread is periodically dried and weighed and it is found the weight ofthe thread remains essentially constant after a few rinses and thatfurther extensive washing with water will not reduce the weight belowabout 1.06 grams which represents a pickup of about 6 percent.

The sustained germicidal activity of the suture is demonstrated byplacing the suture in contact with a micro-organism such as bacillussubtilus. Even after repeated washings, the area around the sutureremains clear. Sustained microbiocidal activity is also demonstrated inmice. Sutures treated according to the invention implanted in mice fordays, for example, show no growth of organism when removed from the miceand placed in a culture medium.

EXAMPLE II A silk suture is treated with an aqueous solution ofbenzalkonium chloride at room temperature and washed until the measuredweight pickup is essentially constant at about 9 per- 1 cent. Sustainedgermicidal activity is demonstrated as in Example I.

EXAMPLE III A collagen suture is provided with about 6 percent ofbenzethonium similarly as in Example 1, except that the collagen sutureis initially preswollen in an aqueous glycerine solution. Thebenzenthonium is very resistant to being leached from the suture andprovides sustained germicidal activity as in the previous examples.

EXAMPLE IV EXAMPLE V A silk suture is immersed in a l0 percent aqueoussolution of dioctyl sodium sulfosuccinate and washed until the pickup ofthe anionic surfactant was essentially constant at about 3 percent byweight. The suture showed sustained germicidal activity as in theprevious examples.

As has been mentioned above, the substrate can be a textile materialwhich can be in the form of a fiber, thread, yarn or finished article.The fiber material can be natural or synthetic. The invention isapplicable to clothing, blankets and other woven and nonwoven fabrics aswell as to threads and sutures and dressings and the like. In additionto the exemplified materials, the substrate may compriseotherproteinacious materials and other amphoteric, nitrogenous organicpolymers. The invention is particularly suited to nonabsorbable suturesand other articles fabricated from materials, such as silk, which arenot absorbed by the host body.

The maximum amount of long-lasting germicidal ion provided in thesubstrate will vary somewhat depending on the substrate. Amounts inexcess of that which will chemically combine with the substrate can beprovided and are desirable where an initial high dosage of germicide isbeneficial In general, the minimum amount of long-lasting germicide islargely a matter of choice, but trace amounts and amounts as low as 0.1percent by weight based on the weight of the fiber, are effective.Although more antibacterial material can be provided in some cases, itis generally not practical to do so since lesser amounts achieve thedesired persistent antibacterial action and the preferred amount ofchemically combined antibacterial material is therefore between 0.1 and15 percent by weight based on the weight of the original substrate.

The persistent germicidal activity of materials provided with insolublegermicide salts according to the invention is demonstrated by placingmaterials treated according to the invention, for instance as in theworking examples, in contact with an organism such as bacillus subtilis.Even after repeated washings the area around a silk thread containingbenzethonium, for example, will remain clear of the organism. Similarly,the persistent germicidal nature of the suture is illustrated by invitro testings, in mice. Silk sutures treated according to theinvention, for example, with benzethonium stearate, after beingimplanted in mice for 5 days, show no growth of organisms when removedand placed in a culture medium.

As mentioned above, the substrates to which the invention is applicable,are amphoteric. The fibroin protein of silk, for example, in its normalsalt form, contains both free amine groups and free carboxyl groups.Many of these groups are undoubtedly present in salt form, the protonsof the carboxyl groups having been transferred to the basic aminogroups. In the presence of strong acids, however, undissociated carboxylgroups exist and, in the presence of strong bases, the amino groups arefree. Hence, the proteins are amphoteric electrolytes. In the presenceof acids, therefore, the proteins are in the form of acid salts whichare'cationic. In this form, the proteins preferentially combine withanions and it is thus preferred, in providing an anionic germicidal ionin the substrate according to the invention, to conduct the process in amedium having a pH below the isoelectric point such that the protein ispresent in the form of its acid salt. Similarly, in I providing acationic germicidal ion, it is preferred to conduct the process in amedium having a pH above the isoelectric point.

Where silk is the substrate, and particularly where an anionic germicideis to be provided in the silk, it is preferable to remove gum from thesilk with degumming agents which can be readily washed out of the silk.Silk is conventionally degummed with soaps which include palmitates,stearates and oleates which may interfere with subsequent chemicalcombination of the silk and the germicidal ion. It is thereforepreferred to degum the silk with a low molecular weight, highly solublealkaline material and inorganic bases, and alkaline salts of lowmolecular weight organic acids having no more than 10 carbon atoms arepreferred such as sodium acetate, ammonium hydroxide, etc. The suture orothersubstrate, such as a bandage, is conveniently sterilized subsequentto incorporation of the germicidal ion therein.

It is also contemplated to provide the substrate with ions in additionto the germicidal ions and it is also possible to provide the substratewith both cationic and anionic germicides. For example, heparin ions canbe provided in a silk or other substrate according to the invention bycontacting the substrate with an aqueous solution thereof. The substrateis thus provided with anticoagulant properties as well as germicidalproperties similarly as in my copending application Ser. No. 648,247,now abandoned. Any combination of anionic and cationic germicides can beprovided in a substrate by treating same sequentially with aqueoussolutions thereof in the manner shown in the examples.

The invention is also suitable in protecting against infection duringsurgery. For example, any suitable substrate of the type mentionedabove, in the form of a mesh or film or the like, may be used to preventinfection in closing a surgical incision by laying down one o ore layersof the treated film or mesh as the incision is closed. After suturing ofthe pertinoneum the exposed area is covered by a layer of treatedsubstrate such as an absorbable collagen film or silk mesh. The fasciais next sutured in the usual manner. The exposed fascia is then coveredby a layer of the treated mesh or layer is placed over the wound.

The toxicity of the germicidal anionic and cationic surface activeagents is well known. Since the chemically combined materials arevirtually insoluble, however, and since the gross amount of materialimplanted in the body in the form of a suture or wound closing mesh isquite small, toxic levels of the materials are never approached. Forexample, in a case requiring a total amount of suture weighing 1 gram,the maximum amount of germicide would be 150 milligrams. If thismaterial were not chemically combined and released rapidly into the areaadjacent the implant, toxic levels of the germicidal ions would not bereached. in the present invention, however, the materials are chemicallycombined with the substrate and are thus only very slowly released overa period of days. In general, the germicidal ions are released veryslowly according to the present invention and preferably at a rate ofnot more than about 1 or 2 milligrams per hour. Accordingly, theconcentrations of germicidal material is well below a level which wouldcause any problem of toxicity.

What is claimed is:

l. A surgical suture having long-lasting germicidal propertiescomprising a strand ofa nitrogenous, umphoteric. organic film-formingmaterial having bonded thereto both cations of an acid antibiotic andanions of a basic antibiotic,

2. The surgical suture of claim 1 wherein the basic antibiotic isselected from the group consisting of gentamicin and polymixin.

3. The surgical suture of claim 1 wherein the basic antibiotic isgentamicin.

4. The surgical suture of claim 1 wherein the basic antibiotic ispolymixin.

5. The surgical suture of claim 1 wherein the acid antibiotic ispenicillin.

6. The surgical suture of claim 1 wherein the penicillin is oxacillin.

7. The surgical suture of claim 1 wherein the basic antibiotic isgentamicin and the acid antibiotic is oxacillin.

8. The surgical suture of claim 1 wherein the basic antibiotic ispolymixin and the acid antibiotic is oxacillin.

9. A surgical suture according to claim 1 wherein the suture is of amaterial selected from silk, collagen and polyvinylpyrollidone.

2. The surgical suture of claim 1 wherein the basic antibiotic isselected from the group consisting of gentamicin and polymixin.
 3. Thesurgical suture of claim 1 wherein the basic antibiotic is gentamicin.4. The surgical suture of claim 1 wherein the basic antibiotic ispolymixin.
 5. The surgical suture of claim 1 wherein the acid antibioticis penicillin.
 6. The surgical suture of claim 1 wherein the penicillinis oxacillin.
 7. The surgical suture of claim 1 wherein the basicantibiotic is gentamicin and the acid antibiotic is oxacillin.
 8. Thesurgical suture of claim 1 wherein the basic antibiotic is polymixin andthe acid antibiotic is oxacillin.
 9. A surgical suture according toclaim 1 wherein the suture is of a material selected from silk, collagenand polyvinyl-pyrollidone.